文章基本信息

标题：Long-Range Coupled Motions Underlie Ligand Recognition by a Chemokine Receptor
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作者：Krishna Mohan Sepuru ; Vinay Nair ; Priyanka Prakash 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：12
页码：1-37
DOI：10.1016/j.isci.2020.101858
语种：English
出版社：Elsevier
摘要：SummaryChemokines are unusual class-A G protein-coupled receptor agonists because of their large size (∼10 kDa) and binding at two distinct receptor sites: N-terminal domain (Site-I, unique to chemokines) and a groove defined by extracellular loop/transmembrane helices (Site-II, shared with all small molecule class-A ligands). Structures and sequence analysis reveal that the receptor N-terminal domains (N-domains) are flexible and contain intrinsic disorder. Using a hybrid NMR-MD approach, we characterized the role of Site-I interactions for the CXCL8-CXCR1 pair. NMR data indicate that the CXCR1 N-domain becomes structured on binding and that the binding interface is extensive with 30% CXCL8 residues participating in this initial interaction. MD simulations indicate that CXCL8 bound at Site-I undergoes extensive reorganization on engaging Site-II with several residues initially engaged at Site-I also engaging at Site-II. We conclude that structural plasticity of Site-I interactions plays an active role in driving ligand recognition by a chemokine receptor.Graphical AbstractDisplay OmittedHighlights•Structural plasticity governs chemokine-receptor interactions•Receptor N-terminal domain captures the chemokine by a fly-casting mechanism•Crosstalk between two distinct binding sites determines recognition and function•A hybrid NMR-MD approach provides crucial insights into receptor binding mechanismComputational Molecular Modelling; Molecular Dynamics; Biochemistry; Structural Biology